Hepatitis B virus (HBV) infection is a worldwide health problem. It causes a wide spectrum of pathologies ranging from inapparent infection to fatal hepatocellular diseases (Tiollais et al., Nature 317:489, 1985). The HBV virion is composed of an envelope, which carries the hepatitis B surface antigen (HBsAg), and a nucleocapsid. The nucleocapsid encloses a circular, partially double-stranded 3.2 kb DNA, which replicates via a RNA intermediate. The nucleocapsid is formed by the hepatitis B core antigen. When virions are present in the blood, an additional soluble antigen related to the nucleocapsid, the hepatitis B e antigen (HBeAg), is generally detected in the serum. Several studies have suggested that HBV is not directly hepatocytopathic and that host immune response to viral antigens presented on the surface of infected liver cells may play an important role in pathogenesis (Mondelli et al., J. Immunol. 129:2773, 1982; Mondelli et al., Arch. Pathol. Lab. Med. 112:489, 1988; Chisari et al., Microb. Pathog. 6:311, 1989).
The lack of suitable animal models for hepatitis B has hindered understanding of the molecular mechanisms responsible for hepatocyte death and viral clearance (Ochiya et al., Proc. Natl. Acad. Sci. USA 86:1875, 1989; Gripon et al., J. Virol. 62:4136, 1988). Germ-line transgenic mouse models have been produced to investigate the pathogenesis of HBV infection, but these animals are immunologically tolerant to HBV antigens and do not spontaneously develop hepatitis (Moriyama et al., Science 248:361, 1990). Hepatitis must be induced in these animals by a complicated, multi-step process involving, e.g., priming lymphocytes with HBV proteins in syngeneic animals and adoptive transfer of the primed cells in vivo (Moriyama et al., supra; Ando et al., J. EXP. Med. 178:1541, 1993).